Weakening and dilation of the main abdominal artery (aortic aneurysm, AAA) affects 5-10% of men and 1% of women aged over 60 years. The weakening process is usually progressive and without surgical repair the artery can burst usually leading to death. Despite improved medical treatment of artery disease the incidence of this problem is increasing. At present no medication has been clearly shown to halt or slow the artery weakening in humans. The aortic weakening results from inflammation, protein degrading enzymes and loss of vascular smooth muscle cells (VSMC). In this study we investigate the role of two calcium-controlling proteins, osteoprotegerin (OPG) and osteopontin (OPN), in human artery weakening. These proteins are of particular interest because preliminary human, animal and cell studies suggest they may be of critical importance in AAA. The role of OPG and OPN in AAA development and progression will be assessed by a combination of human, animal and cell culture experiments. The effect of variation in the OPG and OPN genes on AAA development and progression will be assessed by genetic analysis of DNA from 4045 participants in the Western Australian AAA study. The influence of OPG and OPN on inflammation, protein degrading enzymes and VSMC loss will be studied in cell culture and an animal model of AAA. Finally, two potential medical treatments for AAA will be assessed as to their effect on OPG and OPN utilizing cell culture and animal studies. Understanding the role of these calcium-controlling proteins in artery weakness and how drug therapy can interfere in these effects is an important step in the development of new treatment for aortic aneurysm.